Project Summary/Abstract This application requests continued funding for a pre-doctoral (6 slots, an increase of 2 slots) and post- doctoral (4 slots, remains the same) training grant entitled, `Training in Cardiovascular Translational Research'. The goal is to train future CV scientists who have expertise in bringing basic discoveries from the laboratory into clinical practice through development of novel therapeutics. The KEY INNOVATION is a course covering the major disciplines required for successful therapeutics discovery, validation and development including: 1) basic mechanisms in CV diseases/target identification; 2) drugging the target/high throughput screening; 3) target validation/proof of concept using relevant animal models of human disease; 4) introduction to medicinal chemistry ? optimization of compounds/biologicals; 5) basic concepts of intellectual property protection; 6) fundamentals of medical pharmacology; 6) basics in toxicology; 7) principals of drug development from pre-clinical to IND filing; 8) fundamentals of clinical testing. A new dimension to this highly successful program focuses on structure-based cardiovascular drug discovery. Faculty mentors direct research training in four primary areas: 1) Structural Biology of CV Signaling Molecules, including solving structures of ion channels and G-protein coupled receptors; 2) Biophysics of CV Cell Signaling, including ion channels, cardiac and smooth muscle signaling; 3) Animal Models of CV Diseases, including mice models of heart failure, cardiac arrhythmias, atherosclerosis, and diabetes; and 4) Clinical-Translational CV Sciences, including integrated use of human stem cells, genetics of cardiovascular diseases, biomaterial scaffolds and bioreactors, clinical electrophysiology, and heart failure. Another innovation provides clinical exposure/training for pre- and postdoctoral trainees who are introduced to clinical activities in the hospital under the supervision of cardiology fellows in order to gain appreciation of the relevance of their basic research to human CV disease. Trainees apply for independent funding to continue their training after two years of grant support. Pre-doctoral candidates are selected from a large and diverse pool of outstanding applicants to 7 graduate programs at Columbia University Medical Center? Cellular Physiology and Biophysics, Biochemistry and Molecular Biophysics, Pathology and Cell Biology, the Integrated Program, Nutritional and Metabolic Biology, Pharmacology and Molecular Signaling. Post-doctoral candidates are selected from a large applicant pool of direct applicants to program faculty. Ongoing efforts to recruit of woman and minorities continue to be successful. The training program provides cardiovascular seminar series, journal clubs, joint laboratory meetings and retreats that foster collaborations and interdisciplinary research. The program takes advantage of the many existing strengths of Columbia University, including the Irving Center for Clinical and Translational Research (CTSA), Mailman School of Public Health, Genome Center, Bioinformatics, and Tissue and Biomedical Engineering.